Italian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma
Alessandro BroccoliBeatrice CasadeiAlice MorigiFederico SottotettiManuel GottiMichele SpinaStefano VolpettiSimone FerreroFrancesco SpinaFrancesco PisaniMichele MerliCarlo ViscoRossella PaoliniVittorio Ruggero ZilioliLuca BaldiniNicola Di RenzoPatrizia TosiNicola CascavillaStefano MolicaFiorella IlariucciGian Matteo RigolinFrancesco D’AlòAnna VanazziElisa SantambrogioRoberto MarascaLucia MastrulloClaudia CastellinoGiovanni DesabbataIlaria ScortechiniLivio TrentinLucia MorelloLisa ArgnaniPier Luigi Zinzani
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// Alessandro Broccoli 1 , Beatrice Casadei 1 , Alice Morigi 1 , Federico Sottotetti 2 , Manuel Gotti 3 , Michele Spina 4 , Stefano Volpetti 5 , Simone Ferrero 6 , Francesco Spina 7 , Francesco Pisani 8 , Michele Merli 9 , Carlo Visco 10 , Rossella Paolini 11 , Vittorio Ruggero Zilioli 12 , Luca Baldini 13 , Nicola Di Renzo 14 , Patrizia Tosi 15 , Nicola Cascavilla 16 , Stefano Molica 17 , Fiorella Ilariucci 18 , Gian Matteo Rigolin 19 , Francesco D'Alò 20 , Anna Vanazzi 21 , Elisa Santambrogio 22 , Roberto Marasca 23 , Lucia Mastrullo 24 , Claudia Castellino 25 , Giovanni Desabbata 26 , Ilaria Scortechini 27 , Livio Trentin 28 , Lucia Morello 29 , Lisa Argnani 1 and Pier Luigi Zinzani 1 1 Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy 2 Operative Unit of Medical Oncology, IRCCS Fondazione Maugeri, Pavia, Italy 3 Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 4 Division of Medical Oncology A, National Cancer Institute, Aviano, Italy 5 Department of Hematology, DISM, Azienda Sanitaria Universitaria Integrata, Udine, Italy 6 Division of Hematology, Department of Molecular Biotechnologies and Scienze for Health, University Torino, Torino, Italy 7 Unit of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 8 Hematology and Transplantation Unit, Regina Elena National Cancer Institute, Roma, Italy 9 Unit of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy 10 Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy 11 Hematology Service, Medicine Department, Rovigo Hospital, Rovigo, Italy 12 Division of Hematology, Niguarda Ca' Granda Hospital, Milano, Italy 13 OncoHematology Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy 14 Unit of Hematology, Vito Fazzi Hospital, Lecce, Italy 15 Hematology Unit, Infermi Hospital Rimini, Rimini, Italy 16 IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 17 Unit of Oncology/Hematology, Azienda Ospedaliera "Pugliese-Ciaccio", Catanzaro, Italy 18 Unit of Hematology, Arcispedale Santa Maria Nuova di Reggio Emilia, Reggio Emilia, Italy 19 Unit of Hematology, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy 20 Institute of Hematology, Università Cattolica del Sacro Cuore, Roma, Italy 21 Hemato-Oncology Division, European Institute of Oncology, Milano, Italy 22 Unit of Hematology, University-Hospital Città della Salute e della Scienza di Torino, Torino, Italy 23 Department of Medical Sciences, Hematology Unit, University of Modena and Reggio Emilia, Modena, Italy 24 Unit of Hematology, Ospedale San Gennaro di Napoli, Napoli, Italy 25 Unit of Hematology, Ospedale Santa Croce E Carle, Cuneo, Italy 26 Ematologia Clinica, Ospedale Maggiore, Trieste, Italy 27 Clinica di Ematologia Ospedali Riuniti, Ancona, Italy 28 Unit of Hematology, University of Padova, Padova, Italy 29 Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy Correspondence to: Pier Luigi Zinzani, email: pierluigi.zinzani@unibo.it Keywords: ibrutinib; mantle cell lymphoma; relapsed; refractory; real life Received: January 30, 2018 Accepted: April 07, 2018 Published: May 04, 2018 ABSTRACT Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.Keywords:
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Mantle cell lymphoma (MCL) comprises about 3% of all newly diagnosed non-Hodgkin’s lymphoma cases and is thought to be incurable with conventional chemotherapy [1]. Ibrutinib, approved in Japan in ...
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Mantle cell lymphoma (MCL) accounts for about 5% of all lymphomas. Its clinical and histological features are heterogeneous. After a frequently good initial response, the disease generally and repeatedly relapses and finally the outcome is poor. Particularly severe is the prognosis of the rare occurrence of CNSi (Central Nervous System involvement). Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has shown strong activity in relapsing patients with Chronic Lymphocytic Leukemia (CLL) and MCL. Few reports are available about treatment with ibrutinib of patients presenting CNSi by lymphoproliferative diseases (LPD). In all of them, ibrutinib, at the dosage between 420 and 560 mg/day, showed an impressive effectiveness. Here we describe a case of MCL with CNS relapse showing an excellent response to ibrutinib administered at the unusual dose of 280 mg/day because of concomitant treatment of cardiological disease.
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Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL.
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Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).
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Abstract The U.S. Food and Drug Administration (FDA) approved the targeted therapy ibrutinib for treating patients with mantle cell lymphoma who have received at least one prior therapy. The drug is the second designated by the FDA as a “breakthrough therapy” to be granted approval by the agency.
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For treating relapsed mantle-cell lymphoma (MCL), the Bruton tyrosine kinase inhibitor ibrutinib has been approved in the U.S. and Europe, and the mTOR (mammalian target of rapamycin) inhibitor temsirolimus is approved in Europe. Investigators compared the two drugs in a multinational, open-label trial funded by ibrutinib's manufacturer.
The researchers randomized 280 patients (median age, 68) with relapsed or refractory MCL to …
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